Project Summary Coxsackievirus is a common infection that causes viral myocarditis, meningoencephalitis, and hand, foot, and mouth disease in children and adults. Coxsackievirus is spread by the fecal-oral route and initiates infection in the gastrointestinal tract. There are no therapeutics to Coxsackievirus, in part due to a lack of knowledge in how Coxsackievirus initiates infection in the intestine. We recently developed a mouse model to investigate Coxsackievirus B3 (CVB3) replication in the intestine. Using this model, we found that, similar to humans, male mice succumb to CVB3-induced disease, whereas female mice do not. Intriguingly, CVB3 replication in the intestine of male mice is enhanced compared to female mice. Recent data indicate that non-hormonal factors, such as host genes, play a role in intestinal CVB3 replication. Therefore, the goal of this study is to identify host genes that impact viral replication in the intestine. These studies will shed light on the mechanism of CVB3 replication in the intestine.